The magic dance of the alarmones (p)ppGpp

The alarmones (p)ppGpp are important second messengers that orchestrate pleiotropic adaptations of bacteria and plant chloroplasts in response to starvation and stress. Here, we review our structural and mechanistic knowledge on (p)ppGpp metabolism including their synthesis, degradation and interconversion by a highly diverse set of enzymes. Increasing structural information shows how (p)ppGpp interacts with an incredibly diverse set of different targets that are essential for replication, transcription, translation, ribosome assembly and metabolism. This raises the question how the chemically rather simple (p)ppGpp is able to interact with these different targets? Structural analysis shows that the diversity of (p)ppGpp interaction with cellular targets critically relies on the conformational flexibility of the 3' and 5' phosphate moieties allowing alarmones to efficiently modulate the activity of target structures in a broad concentration range. Current approaches in the design of (p)ppGpp-analogs as future antibiotics might be aided by the comprehension of conformational flexibility exhibited by the magic dancers (p)ppGpp.